Patatin-like phospholipase domain-containing protein 2 (PNPLA2)

Patatin-like phospholipase domain-containing protein 2 (PNPLA2), commonly known as adipose triglyceride lipase (ATGL), is the primary enzyme responsible for the initial step of triglyceride hydrolysis in mammalian cells [1, 2]. It specifically catalyzes the conversion of triacylglycerols to diacylglycerols, releasing a free fatty acid, which is a critical process for energy mobilization during fasting or exercise [2, 4]. PNPLA2 is predominantly expressed in adipose tissue but also plays vital roles in the heart, skeletal muscle, and liver [1]. Genetic deficiency of PNPLA2 leads to neutral lipid storage disease with myopathy (NLSDM), characterized by systemic triglyceride accumulation and muscle dysfunction [1, 4]. Conversely, excessive PNPLA2 activity is associated with elevated plasma free fatty acids, contributing to insulin resistance, type 2 diabetes, and cancer-associated cachexia [3, 4]. Pharmacological modulation of PNPLA2, particularly through small-molecule inhibitors like Atglistatin, is being investigated as a therapeutic strategy to treat metabolic syndrome and fatty liver disease by controlling the flux of fatty acids [3]. References: [1] UniProt (Q96AD5); [2] Zimmermann R, et al. Science (2004); [3] Schweiger M, et al. Nature Communications (2017); [4] Grabner GF, et al. Journal of Lipid Research (2021).

Other names

Adipose triglyceride lipaseATGLDesnutrinTriglyceride hydrolaseCalcium-independent phospholipase A2 antigen-like family member EiPLA2-zetaTransport secretion protein 2TTS2

Inhibition of the lipase catalytic activity to prevent the hydrolysis of triglycerides into diglycerides and free fatty acids, thereby reducing systemic fatty acid flux.